HU189599B - Process for producing amidobenzamide derivatives and pharmaceutical compositions containing them - Google Patents

Description

(57) EXTRACT methyl-aminomethyl-furan-2-ylmethyl-thio) -ethylamine is reacted with benzoic acid (V), wherein A and B are as defined above, in an organic solvent, At a temperature between 0 ° C and the boiling point of the solvent used and, if desired, the resulting compound is converted into its pharmaceutically acceptable salt.

The pharmaceutical compositions of the present invention contain from 10 to 1000 mg of the active ingredient amidobenzamide per dosage unit.

CO-NH-CH ₃ CH ₃ -S-CH ₂

NH-A-B

HjN-CH ₂ CH ₂ S-CHj-4 (^ 1-CHjN ch ₃ ch ₃ ch ₃

CH3 (III) (IV)

COOH (V)

NH-A-B .189,599,

This invention relates to novel histamine H ₂ receptor blocking amidobenzamides and their salts, and to pharmaceutical compositions containing them as active ingredients.

After histamine receptors are H, receptors [Ash and Schild, Brit. J. Pharmac. Chemother. 27, 427 (1966)] and H ₂ receptors (Black et al., Natur. 236, 385 (1972)), and recognizing that selective blocking of H ₂ receptors induces inhibition of gastric secretion, many products have been proposed for histamine H 2 _As antagonists of ₂ receptors (hereinafter "H ₂ blockers"), such compounds as internationally known as burimamide, methamide, cimetidine, ranitidine, thiotidine, etintidine, oxmetidine have been the subject of numerous scientific publications. One of these compounds, cimetidine, is already being used by doctors to treat ulcers.

Each of the aforementioned products is characterized by the presence of a structural moiety of the formula I in its molecule. In the formula, Y is oxygen or sulfur, or represents N-CN or _NO2 target group, and wherein said linear component or closed ring as described for oxmetidin. Thus, all the aforementioned products are characterized in that two geminal nitrogen atoms are attached to the carbon atom.

French Patent No. 2,471,376 discloses and claims benzamides of formula II and their pharmaceutically acceptable salts. The R-dimethylaminopyridine or 1-pyrrolidinyl group, ^R1 and ^R2 are independently hydrogen or C1-3 alkyl; R ^{3 is} hydrogen, optionally substituted with cyano, C 1-3 alkoxy, phenyl or C 1-3 alkyl substituted with 5 or 6 membered heterocyclyl, C 3-6 cycloalkyl, C 2-5 optionally C 1-3 alkoxy. , phenyl or phenoxy-substituted alkenyl, C 6 -C 10, optionally one or two hydroxy, halogen, nitro, sulfamoyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkanoyl, Represents a C 4 -alkoxycarbonyl, C 2 -C 4 dialkylamino or C 1 -C 3 alkanesulfonyl group, or a 5 or 6 membered heterocyclic group which may be optionally oxo, halo, C 1 -C 3 alkyl or 1-C 3 alkyl; It may have a C 3 alkoxy substituent; And X represents oxygen or sulfur.

As described in the aforementioned patent application the compounds of the compounds having formula (II) wherein R is dimethylamino group, R ¹ and R ² are hydrogen, R ³ 4-hydroxyphenyl group, or N- [2- ( 5-dimethylamino-methylfuran-2-yl-methylthio) ethyl] attest 2.54 mg / kg ED _S0 characterized nel gastric acid secretion inhibitory activity in rat -4-sulfamoyl-benzamide oxalate form.

The compounds of formula I which do not contain the structural moiety of the above-mentioned French patent do not include amidobenzamides, i.e. benzamides having an acylamido or sulfonylamido substituent on the benzene ring.

² J

It is also known that histamine EI ₂ receptors are present not only in the gastric mucosa but also in the sinus node, ventricular myocardium and coronary arteries, and that known H ₂ blockers are active at both cardiac and gastric receptors. Therefore, inhibition of cardiac H ₂ receptors can lead to bradycardia and asystolia, which may be a side effect of treating ulcerative diseases with cimetidine (Clinica Terapeutica 96, 81-91, especially page 84, 1981).

Therefore, there is a need for compounds that have a good separation of gastric and cardiac H ₂ receptor blocking activity, with the predominance of the lower, and less severe cardiac side effects.

It has been found that certain novel amidobenzamides, which do not contain the structural moiety of formula (I), have good activity at antagonizing the histamine H ₂ receptors and that this effect is preferably directed towards the gastric receptors.

Surprisingly, it has also been found that the H ₂ blocking effect occurs at a satisfactory level only when the "amido" group is in the meta position on the benzamide phenyl ring.

It has further been found that the new amidobenzamidoknál in question do not appear to compounds of the _H2 blocker, cimetidine are particularly vulnerable to side effects such as antiandromiogén effect.

The present invention therefore relates to a process for the preparation of new amidobenzamides wherein A is CO or SO ₂ and B is C 1 -C 6 alkyl, phenyl, pyridyl, pyridyl-1-oxide, pyrazinyl or thienyl. The process of the invention also comprises the preparation of pharmaceutically acceptable salts of these compounds.

Pharmaceutically acceptable salts include non-toxic salts of mineral or organic acids with one or two basic groups present in the compound of formula (III). These include hydrochloride, hydrobromide, sulfate, succinate, tartrate, citrate, fumarate, maleate, 4,4-methylene bis (3-hydroxy-2-naphthoate), hereinafter "pamoate", 2-naphthalenesulfonate, : "Sun silicate", methanesulfonate, hereinafter "mesylate", p-toluene sulfonate, hereinafter "tosylate", etc.

According to the invention, the compounds of formula (III) are prepared by reacting 2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethylamine (IV) with the benzoic acid (V). with a functional derivative thereof, wherein A and B are as defined above, in an organic solvent at a temperature between 0 ° C and the boiling point of the solvent used. The compound thus obtained is a medicament. it can be converted into its satiety salt.

Suitable functional derivatives include anhydride, mixed anhydride, chloride or an active ester.

A preferred functional derivative of an acid of formula (V) is represented by formula (VI) wherein A and B are as defined above and R 0 is nitrophenyl, methoxyphenyl, trityl or benzhydryl.

. 189 599

The reaction temperature may vary from 0 ° C to the boiling point of the solvent used, but the reaction is usually carried out at room temperature or at 30-50 ° C. The use of a low temperature may be advantageous if the reaction is exothermic, for example when chloride is used as the functional derivative of the benzoic acid of formula (V).

Preferably, the reaction solvent is an alcohol (such as methanol or ethanol) or a halogenated solvent (such as methylene chloride, dichloroethane, chloroform, etc.), but other organic solvents compatible with the reagents used, such as dioxane, tetrahydrofuran or a hydrocarbon (e.g. hexane).

If the reaction produces hydrochloric or other acid, the reaction may be carried out in the presence of a proton acceptor (e.g., an alkali carbonate or a tertiary amine), but the proton acceptor is not essential for the preparation of the final product.

The reaction is advantageously rapid; is usually carried out at room temperature or 30-50 ° C for 2 to 4 hours and can be isolated in the form of the free amidobenzamide (III) in the form of the free base or its salt by conventional means.

The free base can be converted into its pharmaceutically acceptable salt by treatment with an appropriate acid in an organic solvent. When the amidobenzamide of formula (III) is isolated as a salt, the corresponding free base may be cleaved with alkali hydroxide or carbonate.

The compounds of formula (III) of the present invention, as well as their pharmaceutically acceptable salts, exhibit selective antagonism at the histamine H ₂ receptor by selectively inhibiting gastric secretion at the level of the gastric H ₂ receptor, while their activity on the cardiac H ₂ receptor low. They are therefore well suited for the treatment of ulcers.

The selective activity of the products of the present invention on H ₂ type receptors is demonstrated by the absence of H ₁ type activity in histamine-induced contraction of isolated guinea pig ileum.

The antagonistic activity of the amidobenzamides of the present invention towards gastric histamine H ₂ receptors was demonstrated by the Ghosh and Schild method (Brit. J. Pharmacol. 1958, 13, 54) in an experiment in which rats induced hyperamine secretion and tested their secretion. inhibitory effect. According to this experiment, gastric acid hypersecretion is induced by intravenous infusion of histamine at a maximal dose, mcmol / kg / hr, and gastric secretion is measured by passing the animal's stomach at a constant rate of saline.

Table I shows the dose (mcmol / kg, single intravenous administration) of the code-numbered compounds of the present invention and 3 reference compounds that inhibit histamine-induced gastric hypersecretion by 50% (ID ₀ ). . Such an ID ₅₀ represents the index of gastric H ₂ inhibitory activity.

THE/. Reference compounds in Table I:

2-cyano-1-methyl-3- [2 - [(5-methylimidazol-4-yl) methylthio] ethyl] guanidine (hereinafter internationally known as "cimetidine"), N- [2- [ [5 - [(dimethylamino) methyl] furfuryl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine (hereinafter internationally known as "ranitidine"),

N- [2- (5-Dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -4-sulfamoyl-benzamide, as described in ref. French Patent No. 4,684,198 (hereinafter "Compound A").

Table I

Compound id ₅₀ (mcmol / kg) Relative effect (cimetidine = 1) cimetidine 0.95 1.00 ranitidine 0.25 3.80 The compound 2.26 0.42 CM 57822 0.98 0.97 CM 57888 0.63 1:50 SR 57912 0.33 2.88 SR 57922 1.15 0.82 SR 57927 A 1.15 0.82 SR 57933 1.82 0.52 SR 57975 0.93 1.02 SR 57981 A 0.49 1.94

As shown in the table, all derivatives representing the compounds of the present invention are more active than Compound A, and most have activity similar to or superior to cimetidine.

Two products, namely SR 57981 and SR 5791 2, are highly potent and have activity close to ranitidine.

The antagonistic activity of the compounds of the present invention on the cardiac histamine H ₂ receptors was determined by testing for inhibition of histamine-induced increase in the right atrium of the guinea pig [Reinhardt, D. et al., Agents and Actions 4; 217-221 (1974)].

II. Table 4 shows the concentrations of 4 derivatives represented by the compounds of the invention, CM 57822, CM 57888, SR 57912 and SR 57922, as well as the concentrations of cimetidine, ranitidine and Compound A isolated in the right atrium of the guinea pig with histamine 50% (IC ₅₀ ). Such an IC ₅₀ symbolizes the cardiac H ₂ blocking effect.

II. spreadsheet

Compound id ₅₀ (mcmol / kg) Relative effect (cimetidine = 1) cimetidine 4 10 ' ⁷ 1 ranitidine 8 · 10 ” ⁸ 5 The compound 3.1 · 10 ’ ⁷ 1.3 CM 57822 2 · 10 ⁶ 0.2 CM 57888 5.9 · 10 ⁷ 0.67 SR 57912 5 · 10 ⁶ 0.08 SR 57922 6 · 10 ” ⁶ 0.06 ·

189/599

The table shows that all of the representative compounds of the invention the heart is less active as an _H2 blocker such as cimetidine, however, the more active the compound.

Therefore, the compounds of the present invention are distinguished from those known in the art for their H ₂ blocking activity in the heart and stomach in favor of the latter.

The antiandromiogenic activity of a representative of the compounds of the invention, namely CM 57888, was determined with respect to cimetidine and ranitidine in Sprague Dawley rats (Group 9) of immature CD (SD) BR (Charles River-France) strain. The animals were castrated at 22-23 days of age and stimulated by injecting the genital tract and levator ani muscle with testosterone daily.

Testosterone was administered by subcutaneous administration, suspended in steroid diluent, at doses of 0.2 mg / animal / day and 0.4 mg / animal / day. Cimetidine, ranitidine, and CM 57888 were injected intraperitoneally in parallel with each dose of testosterone, suspended in saline for ranitidione, and steroid-soluble for the other two substances; the dose used was 400 mg / kg / day for cimetidine, 100 mg / kg / day for ranitidine and 200 mg / kg / day for CM 57888. As a control, a group of animals treated with solvent alone was used. The treatment lasted for 8 days. Animals were sacrificed 24 hours after the last injection, and the abdominal prostate, seminal vesicle and levator ani muscle were immediately withdrawn and weighed.

The three substances were found to exhibit anti-androgenic and anti-anabolizing activity. However, at the doses used, CM 57888 activity was much lower than that of the reference compounds because, in contrast, the compound of the invention had no effect when testosterone was administered at a dose of 0.4 mg / animal / day. This experiment demonstrates that the compounds of the present invention are less likely to have side effects associated with the known anti-andromiogenic activity of known H ₂ blockers.

In terms of their degree of activity, the compounds of the present invention are barely toxic and have a favorable therapeutic index.

The pharmaceutical compositions of the present invention contain the active ingredient amidobenzamides of formula (III) and pharmaceutically acceptable salts thereof.

For the H ₂ blocking agent of the present invention, the oral, sublingual, subcutaneous, intramuscular, intravenous, rectal, or transdermal dosage forms of the present invention may be administered to the animal or human in the form of a unit dosage form, conventional pharmaceutical excipients, and gastric ulcer.

The daily dose of the active ingredient may vary from 1 to 100 mg / kg body weight, and preferably 10 to 50 mg / kg, to achieve the desired H ₂ blocking effect.

Each dosage unit may contain from 10 to 1000 mg (preferably from 100 to 500 mg) of the active ingredient in admixture with a pharmaceutical excipient. Such a dosage unit may be administered 1 to 4 times daily.

Suitable unit dosage forms include tablets, capsules, powders, granules and solutions or suspensions for oral use, and suppositories, suppositories, and suppositories for parenteral administration. .

When a solid formulation is prepared in the form of a tablet, the active ingredient is formulated with a pharmaceutical excipient such as a pharmaceutical composition. gelatin, starch, lactose, magnesium stearate, talc, acacia, etc. mix. The tablets may be coated with sucrose or other suitable substances, or may be treated to prolong or delay their activity and to release a predetermined amount of the active ingredient.

Capsules are prepared by mixing the active ingredient with a diluent and filling the resulting mixture into soft or hard capsules.

The syrup or elixir preferably contains the active ingredient in combination with an acaloric sweetener, a disinfectant with methyl paraben and propyl paraben, and a flavoring agent and a suitable coloring agent.

Water dispersible powders or granules contain the active ingredient in admixture with dispersing or wetting agents, suspending agents (such as polyvinylpyrrolidone, etc.) and sweetening or flavoring agents.

For rectal administration, suppositories (for example, cocoa butter or polyethylene glycols) with meltable binders are prepared.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersing and / or wetting agents, e.g. propylene glycol or butylene glycol.

The active ingredient may also be formulated as microcapsules, optionally with one or more carriers or excipients.

The invention is illustrated by the following examples, without limiting the scope of the invention to the examples;

Example 1

4- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethylamine (4.3 g, 0.02 mol) and 4-nitrophenyl-3-acetamido- (6 g, 0.02 mol). The benzoate mixture was stirred in 150 ml of methanol at 40 ° C for 2.5 hours. The solvent was evaporated under reduced pressure and the residue was evaporated. dissolve in 100 ml of N hydrochloric acid. The acidic solution was washed with ethyl acetate (2 x 40 mL) and the pH adjusted to 7.8 with sodium hydroxide. The product was thoroughly extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in 20 ml of isopropanol and the resulting solution was poured into a solution of 1.7 g of anhydrous oxalic acid in 20 ml of isopropanol. The precipitate was filtered off and crystallized from ethanol. This way

189,599 g of 3-acetamido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide oxalate are obtained. Code Number: CM 57820. Mp .: 123-126 'C.

If, by the same method, 0.02 mol of 2- (5-dimethylaminomethyl-furan-2-ylmethylthio) -ethylamine with 0.02 mol of 4-nitrophenyl-3-propionamidobenzoate, 0.02 mol of with nitrophenyl-3-butyramido-benzoate and 0.02 mol of 4-nitrophenyl-3-trimethylacetamido-benzoate, 3-propionamido-N- [2- (5-dimethylaminomethyl-furan); 2-ylmethylthio) ethyl] benzamide oxalate (m.p. 133-135 ° C);

3-Butyramido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide oxalate (m.p. 125-127 'C); and 3-trimethylacetamido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide oxalate (m.p. 153-155 'C).

Example 2

2- (5-Dimethylaminomethyl-furan-2-ylmethyl-thio) -ethylamine (0.02 mol) and 4-nitrophenyl-3-methanesulfonamido-benzoate (0.02 mol) were dissolved in methanol (150 ml). solution at 45 ° C for 2 hours. The solvent was evaporated under reduced pressure and the residue was taken up in 100 ml of N hydrochloric acid. The acidic solution was washed with ethyl acetate and the pH was adjusted to 7.5 with sodium hydroxide. The product is thoroughly extracted with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate, the solvent is evaporated under reduced pressure and the residue is dissolved in 20 ml of warm isopropanol. 3-Methanesulfonamido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide is obtained. After crystallization from isopropanol, the product melts at 109-111 ° C.

If by the same method 0.02 mol of 2- (5-dimethylaminomethyl-furan-2-ylmethylthio) -ethylamine with 0.02 mol of 4-nitrophenyl-3-ethanesulfonamidobenzoate or 0 , 02 moles of 4-nitrophenyl-3-butanesulfonamidobenzoate,

3-Ethanesulfonamido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide;

3-Butanesulfonamido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide is isolated, which is isolated as oxalate in Example 1. SR 57981 A, mp 103-110 ° C.

Example 3

0.05 mol of 3-benzenesulfonamidobenzoic acid and 0.05 mol of 4-nitrophenol are dissolved in 250 ml of anhydrous methylene chloride and 0.05 mol of dicyclohexylcarbodiimide are added. The mixture was refluxed for 4 hours and then concentrated under reduced pressure. The residue was taken up in 300 ml of methanol and 0.05 mol of 2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethylamine were added. The reaction mixture was refluxed for 2 hours and then concentrated to dryness under reduced pressure. The residue was dissolved in 150 ml of N hydrochloric acid and 100 ml of ethyl acetate and filtered. The organic layer was separated, the aqueous layer was adjusted to pH 7.8 and extracted well with ethyl acetate. The organic phases were collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was taken up in 40 ml of isopropanol. 9.1 g of 3-benzenesulfonamido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide are obtained, code number 577888. The 121'C's are.

By the same method

G, 05 moles of 3- (3-pyridinesulfonamido) -benzoic acid and 3- (2-thiophenesulfonamido) -benzoic acid with 0.05 mol of 4-nitrophenol in 250 ml of anhydrous methylene chloride, 0.05 mol of dicyclohexylcarbodiimide in the presence of ethyl acetate and treating the resulting active ester with 0.5 mol of 2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethylamine 3- (3-pyridinesulfonamido) -N- [2 - 5-Dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide (SR 57933) is isolated from diethyl ether as a glassy solid, m.p. 80-83 ° C (dec.); and 3- (2-thiophenesulfonamide) -N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio'-ethyl] -benzamide, SR 57975, crystallized from ethyl acetate, m.p. 113-115'C.

Example 4

1-3. 0.02 moles of 2- (5-dimethylaminomethyl-furan-2-ylmethylthio) -ethylamine, 0.02 moles, from 0.02 moles of 3-benzamidobenzoic acid and 0.02 moles, as described in Example 2

The active ester formed from 4-nitrophenol in the presence of dicyclohexylcarbodiimide. 3-Benzimido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide (SR 57916) is obtained. After crystallization from ethyl acetate, m.p. 112-115 ° C.

Similarly, 2- (5-dimethylaminomethyl-furar-2-ylmethyl-thio) -ethylamine 3- (2-thienylcarboxamido) benzoic acid, 3- (3-pyridine-carboxamido) benzoic acid With 3- (4-pyridine-carboxamido) -benzoic acid, 3- (2-pyridine-carboxamido) -benzoic acid,

Reaction with 3- (2-pyrazinecarboxamido) -benzoic acid or the active ester of these derivatives gives the following compounds:

(2-thienyl-carboxamido) -N- [2- (5-dimethylaminomethyl-furan-2-yl-methylthio) ethyl] benzamide,

SB 57922, m.p. 116-118 ° C;

3-β-pyridine-carboxamido) -N- [2- (5-dimethylaminomethyl-furanylmethyl-thio) -ethyl] -benzamide dioxalate,

SB 57927 A, crystallized from 95% ethanol, m.p. 137-140 ° C;

3- (4-Pyridine-carboxamido) -N- [2- (5-dimethylamino-pyrkyl-furan-2-ylmethyl-thio) -ethyl] -benzamide dioxalate, SB 57944 A, crystallized from 95% ethanol 175-178 ° C;

3- (2-Pyridine-carboxamido-N- [2- (5-dimethylamino-methyl-furan-2-ylmethyl-thio) -ethyl] -benzamide oxalate, SB 57953 A, crystallized from ethanol, m.p. 143-145 ° C and

I.2-pyrazin-3-carboxamido) -N- [2- (5-dimethylaminomethyl-furan-2-yl-methylthio) ethyl] benzamide,

SF. 57939, m.p. 80-82 'C.

185,599,

Example 5

To a suspension of 9.5 g (0.037 mol) of 3 - [(3-pyridine-1-oxide) carboxamido] benzoic acid and 5 g (0.037 mol) of 4-nitrophenyl in 400 ml of anhydrous methylene chloride was added 7.7 g of Dicyclohexylcarbodiimide (0.037 mol) was added. The mixture was refluxed for 4 hours and then concentrated under reduced pressure. The residue was taken up in 300 mL of methanol and added to the resulting solution

2- (5-Dimethylaminomethyl-furan-2-ylmethyl-thio) -ethylamine (7.9 g, 0.037 mol) was added. The reaction mixture

After 2.5 hours at 40 ° C, it is evaporated to dryness under reduced pressure. The residue was carefully taken up in 70 ml of water and the pH was adjusted with hydrochloric acid in strongly acidic and the solution of ethyl acetate and washed with a mixture of 1: ¹⁵ ethanol 9th The organic phases are collected, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was taken up in 10 ml of acetone. Thus 0.3 g of 3 - [(3-pyridin-l-oxide) ²⁰ xamido carbonyl] -N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) ethyl] benzamide (code number SR 57912) is obtained. 160-162 ° C.

By the same method, 0.037 mol of 2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethylamine

0.037 mol of 3 - [(4-pyridine-1-oxide) carboxamido] benzoic acid and 0.037 mol of 4-nitrophenol in the presence of dicyclohexylcarbodiimide in the presence of 3 - [(4-pyridine 1-oxide) carboxamido] - N- [2- (5-Dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide (SR 57937), m.p. 145-147 ° C after recrystallization from isopropanol, is obtained. .

Example 6 To a solution of 3-benzenesulfonamido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide in 15 ml of ethanol, 0.3 g of oxalic acid 10 40 ml slurry in ethanol. The precipitated salt was filtered off, dried and crystallized from 10 ml of 95% ethanol. 1 g of 3-benzenesulfonamido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethylthio) -ethyl] -benzamide oxalate is obtained in the form of a glassy solid.

Example 7 To a solution of 3-butanesulfonamido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamidoxalate in 10 ml of water was added sodium hydroxide until the pH was will. The mixture was extracted with ethyl acetate: ethanol (9: 1), the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. 1.5 g of 3-butanesulfonamido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide are obtained in the form of a yellowish oil. 60

IR: 3500, 3000, 1660 and 1148 cm ^1st

1 H-NMR (solvent: DMSO-d ₆ / δTMS (ppm): 0.83 (3H, m -?), 1.1-1.8 (4H, m), 2.11 (6H, s) , 2.63 (2H, m-> t), 2.9-3.6 (4H, m), 3.34 (2H, s), 3.75 (2H, s),

6.15 (2H, m), 6.2-6.8 (4H, m), 8.5 (1H, tb, addition of D ₂ O).

Example 8

1-7. tablet containing one of the products described in the example and having the following composition:

active substance 100 mg lactose 70 mg potato starch 40 mg polyvinylpyrrolidone 8 mg magnesium stearate 2 mg

The mixture of the active ingredient, lactose and potato starch was moistened with a 15% alcoholic solution of polyvinylpyrrolidone, the resulting granules were sieved through a 1 mm sieve, magnesium stearate was added and compressed to form tablets. Weight of one tablet: 220 mg.

Example 9

The tablets of Example 8 are coated with sugar and talc in a known manner and the finished pills are polished with beeswax. Weight of one pill: 300 mg.

Example 10

1-7. Capsules containing one of the products described in Examples 1 to 3, containing 200 mg corn starch 90 mg talc 10 mg

The active ingredient and the binders are thoroughly mixed and the resulting mixture is filled into size 1 gelatin capsules. Each capsule contains 300 mg.

Example 11

1-7. Suppositories containing 300 mg of the active ingredient (Witespol W 45) 1450 mg

The finely divided active ingredient is suspended at 37 ° C in the suppository mass and poured into slightly cooled molds. Weight of one suppository: 1750 mg.

Example 12

1-7. containing one of the products described in Examples 1 to 4, having the following composition:

active substance 150 mg microcrystalline cellulose 75 mg lactose 100 mg magnesium stearate 7 mg talc 18 mg

J89 599

The powders are sieved through a 0.3 mm sieve and the components are blended until a homogeneous mixture is obtained, which is compressed and granulated. The resulting granules are compressed into tablets. Weight of one tablet: 350 mg.

Example 13

Following the procedure described in Example 12, the compounds of Examples 1-7. A tablet containing one of the products described in Example ^{10 is} prepared and has the following composition:

agent 350 mg microcrystalline cellulose 100 mg lactose 125 mg magnesium stearate 10 mg talc 15 mg Each tablet weighs 600 mg. Example 14 1-7. The products described in Example one of containing tablets of the following composition: agent 150 mg microcrystalline cellulose 75 mg talc 15 mg polyvinylpyrrolidone 30 mg precipitated silica 25 mg magnesium stearate 5 mg

With the exception of the lubricant, all the ingredients are thoroughly mixed in a mixer for 15 minutes, and the mixture is cured by the gradual addition of water. The mass is sieved through a 1.25 mm sieve.

The particles are dried in a fluidized bed until a suitable moisture content (about 2% water) is formed.

The lubricant is added to the homogeneous mass and tablets are compressed. Each tablet weighs 300 mg.

In the same way, tablets containing 250 mg of active ingredient can be prepared. 40

Example 15

In the same manner as in Example 14, Examples 1-7 are obtained. A tablet containing one of the products described in Example 1 was prepared.

active ingredient 150 mg carboxymethyl starch 10 mg microcrystalline cellulose 85 mg lactose 135 mg hydrogenated castor oil 10 mg magnesium stearate 5 mg

The resulting tablet is coated with the following film composition:

butyl phthalate 0.300 mg diethylaminoethyl butyl polymethacrylate 1.850 mg polyethylene glycol 1500 0.080 mg precipitated silica 0.020 mg talc 0.900 mg titanium dioxide 1.850 mg

The film coating is accomplished by dissolving the above components in a solvent and evaporating the solvent in a fluidized bed. Weight of one tablet: 400 mg.

Patent claims

Claims (7)

A process for the preparation of novel amidobenzamides of formula III wherein A is -CO or -SO ₂ and B is C 1 -C 6 alkyl, phenyl, pyridyl, pyridyl 1-oxide, pyrazinyl or and a pharmaceutically acceptable acid addition salt thereof, wherein 2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethylamine of formula (IV) is a compound of formula (V): reacting a functional derivative of benzoic acid, wherein A and B are as defined above, in an organic solvent at a temperature between 0 ° C and the boiling point of the solvent used, and optionally isolating or liberating the base and, if desired, the pharmaceutically acceptable base. to form their salt, (Priority: 07/07/1982) 2. The process of claim 1, wherein the cmidobenzamide of formula (III) is salted in the form of a salt thereof and the free base is neutralized by salting with an alkali metal hydroxide or carbonate. (Priority: 07/07/1982) 3. A process for the preparation of a histamine H ₂ receptor blocking medicament comprising mixing 10-1000 mg of the amidobenzamide prepared according to claim 1 per dosage unit with a pharmaceutical carrier. (Priority: 07/07/1982) 4. The method of claim 3 wherein the amount of active ingredient is 100 to 500 mg per dosage unit. (Priority: 07/07/1982) 5. A process for the preparation of amidobenzamides of formula (III) wherein A is -CO or -SO, B is (C 1 -C 6) -alkyl, and pharmaceutically acceptable acid addition salts thereof, characterized in that the 2- (5-dimethyl) -aminomethyl] -furan-2-ylmethylthio) ethylamine is reacted with a benzoic acid of the formula V in which A and B are as defined above in an organic solvent at 0 ° C and at the boiling point of the solvent used and optionally converting the resulting compound into a pharmaceutically acceptable salt thereof. (Priority: 08/08/1981) 6. A process for the preparation of the amidobenzamides of formula (II) wherein A is -CO or -SO ₂ , B is phenyl, or a pharmaceutically acceptable acid addition salt thereof, characterized in that the 2- (5-dimethylamino) N, N-furan-2-ylmethylthio) ethylamine is reacted with a functional derivative of a benzoic acid of formula (V) wherein A and B are as defined above in an organic solvent at a temperature between 0 ° C and the boiling point of the solvent used. and, if desired, converting the resulting compound into a pharmaceutically acceptable salt thereof. (Priority: October 23, 1981) 7. A process for the preparation of amidobenzamides of formula III wherein A is -CO, B is pyridyl-1-oxide and pharmaceutically acceptable acid addition salts thereof.